Broad Spectrum Anticancer Activity of Myo-Inositol and Inositol Hexakisphosphate

Abstract

Inositols (myo-inositol and inositol hexakisphosphate) exert a wide range of critical activities in both physiological and pathological settings. Deregulated inositol metabolism has been recorded in a number of diseases, including cancer, where inositol modulates different critical pathways. Inositols inhibit pRB phosphorylation, fostering the pRB/E2F complexes formation and blocking progression along the cell cycle. Inositols reduce PI3K levels, thus counteracting the activation of the PKC/RAS/ERK pathway downstream of PI3K activation. Upstream of that pathway, inositols disrupt the ligand interaction between FGF and its receptor as well as with the EGF-transduction processes involving IGF-II receptor and AP-1 complexes. Additionally, Akt activation is severely impaired upon inositol addition. Downregulation of both Akt and ERK leads consequently to NF-kB inhibition and reduced expression of inflammatory markers (COX-2 and PGE2). Remarkably, inositol-induced downregulation of presenilin-1 interferes with the epithelial-mesenchymal transition and reduces Wnt-activation, β-catenin translocation, Notch-1, N-cadherin, and SNAI1 release. Inositols interfere also with the cytoskeleton by upregulating Focal Adhesion Kinase and E-cadherin and decreasing Fascin and Cofilin, two main components of pseudopodia, leading hence to invasiveness impairment. This effect is reinforced by the inositol-induced inhibition on metalloproteinases and ROCK1/2 release. Overall, these effects enable inositols to remodel the cytoskeleton architecture.

Figure 1

Inositol mechanisms of action in cancer cells. Inositols (INS), including InsP6 and myo-Ins, modulate a number of different critical pathways. Available data suggest that the inhibition of the phosphorylation-based (P) activation of key molecular targets represents a basic mechanism through which inositol interferes with specific biological functions, eventually ending up in delaying cell replication and in fostering apoptosis or phenotypic differentiation. (A) Inositols inhibit pRB phosphorylation, thus fostering the pRB/E2F complexes formation and blocking further progression along the cell cycle. (B) Phosphatidylinositol-4,5-bisphosphonate (PIP2) is metabolized to diacylglycerol (DAG) and Ins-trisphosphate (IP3) by phospholipase-C (PLC). Moreover, PI3K catalyzes the synthesis of PIP3 from PIP2. PIP3 is required for enabling the activation of ERK and Akt pathways. Indeed, by reducing both PI3K levels and its activity, inositols counteract the activation of the PKC/RAS/ERK pathway. Upstream of that pathway, inositols disrupt the ligand interaction between FGF and its receptor (FGF-r) by interfering with syndecan (Synd) activity as well as with the EGF-transduction processes involving IGF-II receptor and AP-1 complexes. Downstream of PI3K inhibition, Akt activation through selective phosphorylation promoted by PDK and mTORC2 is severely impaired upon inositol addition. Downregulation of both Akt and ERK leads consequently to NF-kB inhibition and reduced expression of inflammatory markers, like COX-2 and PGE2. Inositol-induced downregulation of presenilin-1 (PS1), when associated with inhibition of the PI3K/Akt pathway, counteracts the epithelial-mesenchymal transition (EMT), thus reducing Wnt-activation, β-catenin (β-cat) translocation, Notch-1, N-cadherin (N-cad), and SNAI1 release. Inositols interfere also directly with different cytoskeleton components by upregulating Focal Adhesion Kinase (FAK) and E-cadherin (Ec) and decreasing Fascin (F) and Cofilin, two main components of the pseudopodia. Reduced formation of membrane ruffling and pseudopodia, as well as inhibited release of metalloproteinases (MMPs), severely impairs both motility and invasiveness of cancer cells. This effect is reinforced by the inositol-induced inhibition on ROCK1/2 release, as well as by the decreased levels of phosphorylated Myosin Light Chain (MLC). Overall, these effects enable inositols to remodel F-actin (A) assembly and thus to reshape the cytoskeleton architecture. Blue arrow indicates promoting effect; red line with bar indicates inhibitory effect.